CN107602399B - Preparation method of enkephalinase inhibitor intermediate - Google Patents
Preparation method of enkephalinase inhibitor intermediate Download PDFInfo
- Publication number
- CN107602399B CN107602399B CN201610540043.8A CN201610540043A CN107602399B CN 107602399 B CN107602399 B CN 107602399B CN 201610540043 A CN201610540043 A CN 201610540043A CN 107602399 B CN107602399 B CN 107602399B
- Authority
- CN
- China
- Prior art keywords
- methyl
- compound
- reaction
- formula
- biphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a preparation method of an intermediate of a enkephalinase inhibitor, which takes a compound shown in a formula IV as a starting material, and obtains a target compound shown in a formula I through a few steps of reaction, wherein the compound shown in the formula I can be used for preparing an enkephalinase inhibitor drug Sacubtril.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a enkephalinase inhibitor intermediate.
Background
LCZ696(Entresto, Scheme 1) is an original new compound drug developed by Nowa company. The medicine is prepared by inhibiting Sacubitril and angiotensin receptor blocker Valasartan by enkephalinase in a ratio of 1: 1, approved by the FDA at 7 months of 2015 for marketing in the united states for treatment to reduce the risk of cardiovascular death and hospitalization for heart failure and to reduce ejection fraction in patients with chronic heart failure (NYHA class II-IV). The medicine has good safety and obvious curative effect, is a serious medicine for treating heart failure diseases, is a great breakthrough in the field of heart failure treatment in the past 25 years, and has good market prospect.
Scheme 1: entresto's structure
The method for synthesizing the Sacubtril mainly comprises the following steps:
the method comprises the following steps: document j, med, chem. 1995, 38, 1689-1700 reports a synthetic route (Scheme 2) in which a target product is obtained by performing nearly ten reactions such as Suzuki coupling reaction, Witting reaction, hydrogenation, and the like using D-tyrosine as a starting material. The method has the disadvantages that the raw materials such as expensive unnatural amino acid, trifluoromethanesulfonic anhydride and arylboronic acid are used, and the line is long, so that the cost of the product is high and the product price is high.
Scheme 2: synthetic method I of Sacubitril
And a second synthesis method comprises the following steps: document WO2014/032627 reports a new method (Scheme 3) for synthesizing Sacubitril from 4-bromobiphenyl and S-epichlorohydrin by Grignard reaction, mitsunobu reaction, oxidation reaction, Witting reaction and hydrogenation reaction, wherein the cost of the circuit has obvious advantages compared with that of the first circuit, but the steps are still longer.
Scheme 3: synthetic method II of Sacubitril
The third synthesis method comprises the following steps: documents WO2011/035569 and WO2015/024991 report a method for synthesizing Sacubitril by asymmetric catalytic hydrogenation, in the method, 4-biphenylcarboxaldehyde is synthesized by taking 4-bromobiphenyl as a raw material, dehydroamino acid (Scheme 4) is synthesized by an Erlenmeyer reaction, and the dehydroamino acid and hydrogen undergo asymmetric hydrogenation under the catalysis of a chiral catalyst to obtain a key chiral intermediate.
Scheme 4: synthetic method III of Sacubitril
The method has certain novelty, but the steps are longer, more than ten steps are needed for synthesizing the final product, and the cost is not obviously superior to that of the second line because the chiral rhodium catalyst with high price is used.
Disclosure of Invention
The invention discloses a preparation method of an endorphin inhibitor intermediate, and particularly provides a preparation method of a novel endorphin inhibitor Sacubitril, wherein the method takes a compound shown as a formula IV as a starting material, and obtains an intermediate 2-methyl-4-carbonyl-5- (4' -biphenyl) pentanoic acid or ester (a compound shown as a formula II) through a few steps, and the compound shown as the formula II is processed by the following steps: 1) chiral phenylethylamine induced reductive amination and debenzylation reaction, or 2) carrying out reductive amination with ammonia gas and then using chiral acid for resolution, or 3) carrying out reductive amination reaction catalyzed by a chiral ruthenium catalyst, or 4) carrying out a biological catalysis method and the like to obtain the compound shown in the formula I.
Wherein R is H, methyl, ethyl or other lower alkyl.
Compared with the route reported by the prior document, the route of the invention is from the starting material to the target product, and then the target product is used for preparing the coffee peptidase inhibitor drug Sacubitril.
Detailed Description
Example 1: synthesis of 4-biphenylacetyl chloride
Synthetic reference to 4-biphenylacetyl chloride methods of Bioorganic and Medicinal Chemistry, 2006, vol.14, p.6640-6658. Adding 106g (0.5mol) of 4-biphenylacetic acid, 1.8g (0.025mol) of N, N-dimethylformamide and 400mL of dichloromethane into a 1L three-necked bottle, cooling to 0-10 ℃ in an ice water bath, dropwise adding 78g (0.65mol) of thionyl chloride, removing the ice water bath after dropwise adding, and heating to reflux reaction for 16 hours. The solvent was distilled off under reduced pressure, 150mL of n-heptane was added to the remaining oil after distillation, heated to 55. + -. 5 ℃ to dissolve it, then cooled to 5 ℃ to crystallize, filtered and dried under reduced pressure at 40 ℃ to give 103.8g of an off-white solid with a yield of 90%.
Example 2: synthesis of ethyl 3-carbonyl-4- (4' -biphenyl) butyrate
Synthetic references to ethyl 3-carbonyl-4- (4' -biphenyl) butyrate j., Am, chem., soc. 2006,6893-6902 methods. A500 mL three-necked flask was charged with 46g (0.2mol) of 4-biphenylacetyl chloride, and 250mL of methylene chloride was added and dissolved with stirring to obtain a clear solution. 29g (0.2mol) of Meldrum's acid and 52g (0.4mol) of diisopropylethylamine were added to the reaction flask. Keeping the temperature at 25 +/-5 ℃ for reaction for 2 h. The reaction solution was washed with 0.1M hydrochloric acid, brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid. The yellow solid was transferred to a 250mL three-necked flask, 150mL of absolute ethanol was added, and the reaction was refluxed for 4 hours. After the reaction was complete, the reaction solution was cooled to 0 ℃, the yellow solid was collected by filtration, washed with cold ethanol and dried to give 48g of yellow solid with a yield of 85%.
Example 3: synthesis of ethyl (2R) -2-methyl-3-carboxylate-4-carbonyl-5- (4' -biphenyl) pentanoate
Synthesis of ethyl (2R) -2-methyl-3-carboxylate-ethyl 4-carbonyl-5- (4' -biphenyl) valerate reference Synthesis, 1991, p162-164 method.
Example 3.1: 14g (0.05mol) of ethyl 3-carbonyl-4- (4' -biphenyl) butyrate, which is the compound obtained in example 2, and 150mL of tetrahydrofuran were added to a 250mL three-necked flask, stirred and dissolved, cooled to 0 ℃ in an ice-water bath, 6.7g (0.06mol) of potassium tert-butoxide were added, stirred and reacted for 2 hours, 20.4g (0.075mol) of a 50mL tetrahydrofuran solution of ethyl (R) -2-p-toluenesulfonyloxypropionate was added dropwise, and after the dropwise addition, stirring was continued until the reaction was complete. Adding glacial acetic acid to adjust the pH value of the reaction solution to 4-5, filtering, distilling the filtrate under reduced pressure to obtain yellow oily liquid, and separating and purifying the residue for direct use in the next reaction.
Example 3.2: 100mL of tetrahydrofuran and 2.5g (0.06mol) of 60% sodium hydride were added to a 250mL three-necked flask, and the mixture was cooled to 0. + -. 5 ℃ in an ice-water bath. A mixed solution of 14g (0.05mol) of ethyl 3-carbonyl-4- (4' -biphenyl) butanoate, the compound obtained in example 2, and 20.4g (0.075mol) of ethyl (R) -2-p-toluenesulfonyloxypropionate in 100mL of tetrahydrofuran was added dropwise thereto, and after the addition was completed, the reaction was stirred until completion. Transferring the reaction mixture into ice water in batches for quenching, adjusting the pH value of the reaction solution to 4-5 by using acetic acid, standing, demixing, extracting the water phase by using 100mL of methyl tert-butyl ether, combining organic phases, distilling under reduced pressure to obtain yellow oily liquid, and directly using the yellow oily liquid for the next reaction.
Example 3.3: 14g (0.05mol) of ethyl 3-carbonyl-4- (4' -biphenyl) butyrate, which is the compound obtained in example 2, and 150mL of tetrahydrofuran were added to a 250mL three-necked flask, stirred and dissolved, cooled to 0. + -. 5 ℃ in an ice-water bath, and then 3.3g (0.06mol) of sodium methoxide was added, and after stirring and reacting for 2 hours, a solution of 20.4g (0.075mol) of ethyl (R) -2-p-toluenesulfonyloxypropionate in 50mL of tetrahydrofuran was added dropwise, and after the dropwise addition was completed, stirring was continued until the reaction was completed. Adding glacial acetic acid to adjust the pH value of the reaction solution to 4-5, filtering, distilling the filtrate under reduced pressure to obtain yellow oily liquid 3, and separating and purifying the residue for direct use in the next reaction.
Example 4: synthesis of (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) pentanoic acid or ester
Example 4.1: synthesis of (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) pentanoic acid
To 10g of the compound ethyl (2R) -2-methyl-3-carboxylate-4-carbonyl-5- (4' -biphenylyl) valerate obtained in example 3 were added 6mL of tert-butanol and 35mL of 4M hydrochloric acid, and the above mixture was heated to reflux. After the reaction is finished, cooling to 5 +/-5 ℃ for crystallization, filtering to obtain a crude product of (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valeric acid, and then recrystallizing with toluene to obtain a target product with the purity of more than 98%.
Example 4.2: synthesis of (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate
To 10g of the compound ethyl (2R) -2-methyl-3-carboxylate-4-carbonyl-5- (4' -biphenylyl) valerate obtained in example 3 were added 6mL of tert-butanol and 35mL of 4M hydrochloric acid, and the above mixture was heated to reflux. After the reaction is finished, cooling to 5 +/-5 ℃ for crystallization, filtering to obtain a crude product of (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valeric acid, and then recrystallizing with toluene to obtain a product with the purity of more than 98%.
Esterifying the above product with methanol or ethanol or lower alkyl alcohol to obtain methyl (2R) -2-methyl-4-carbonyl-5- (4 ' -biphenyl) valerate or ethyl (2R) -2-methyl-4-carbonyl-5- (4 ' -biphenyl) valerate or lower alkyl (2R) -2-methyl-4-carbonyl-5- (4 ' -biphenyl) valerate.
Example 5: synthesis of (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid
Example 5.1: to the autoclave were added 10g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid compound obtained in example 4, followed by 100mL of a saturated methanolic ammonia solution, 1g of 10% palladium on carbon. Heating to 45 +/-5 ℃ for reaction, after the reaction is finished, carefully discharging gas in the kettle, taking out reaction liquid, filtering, dropwise adding an aqueous solution of D-tartaric acid into the filtrate, stirring for reaction for 2 hours, filtering, washing a filter cake with methanol, and recrystallizing the filter cake for 2 times with methanol and water to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) valeric acid with the optical purity of more than 98%.
Example 5.2: using the method of example 5.2, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a pressure cooker.
Example 5.3: into a reaction flask were charged 15g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 7.0g of (R) -phenethylamine, 100mL of dichloromethane, and then 22.4g of NaBH (OAc) was added in portions3The temperature is controlled to be 25 +/-5 ℃ and the reaction is carried out for 24 hours. Adding 30mL of water into the reaction solution, stirring, standing for layering, collecting the lower organic phase, distilling under reduced pressure to remove the solvent, adding methanol into the residue for dissolving, transferring the methanol solution into a reaction kettle, adding 1.5g of 10% palladium carbon, and filling hydrogen to 1.0Controlling the temperature to be 25 +/-5 ℃ and reacting for 8h under +/-0.5 MPa. Filtering, concentrating the filtrate to obtain a crude product of (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) valeric acid, and recrystallizing the crude product with methanol and water to obtain a target product with the optical purity of 97%.
Example 5.4: using the method of example 5.3, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a pressure cooker.
Example 5.5: 20g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 20g of ammonium acetate and 120mL of methanol were charged in an autoclave, and after dissolving with stirring, the atmosphere in the autoclave was replaced with nitrogen, and then 0.59g of Ru [ (S) -BINAP (OAc) was added2]Replacing the gas in the reaction kettle with hydrogen, charging hydrogen to 2 +/-0.5 MPa, heating to 55 +/-5 ℃ and reacting for over 36 hours. Cooling to 20 deg.C, carefully discharging the gas in the kettle, transferring the reaction solution to a flask, evaporating the solvent under reduced pressure, adding methyl tert-butyl ether to the residue, heating to 40 deg.C, stirring for 2 hr, cooling, filtering, and washing the filter cake with methyl tert-ether to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid as white solid with optical purity of 81%.
Example 5.6: using the method of example 5.5, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a pressure cooker.
Example 5.7: 15g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 20g of ammonium acetate and 120mL of methanol were charged in an autoclave, and after dissolving with stirring, the atmosphere in the autoclave was replaced with nitrogen, and then 0.59g of Ru [ (S) -BINAP (OAc) was added2]Replacing the gas in the reaction kettle with hydrogen, charging hydrogen to 6 +/-0.5 MPa, heating to 80 +/-5 ℃ and reacting for 24 hours. Cooling to 20 deg.C, carefully discharging the gas in the kettle, transferring the reaction solution to a flask, removing the solvent by evaporation under reduced pressure, adding methyl tert-butyl ether into the residue, heating to 40 deg.C, stirring for 2 hr, cooling, filtering, washing the filter cake with methyl tert-ether,to obtain white solid (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) valeric acid with optical purity of 80%.
Example 5.8: 15g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 20g of ammonium acetate and 120mL of methanol were charged in an autoclave, and after dissolving the mixture by stirring, the atmosphere in the autoclave was changed with nitrogen gas, and then 0.5g of Ru (OAc) was added2[(S)-MeO-BIPHEP]Replacing the gas in the reaction kettle with hydrogen, charging hydrogen to 2 +/-0.5 MPa, heating to 60 +/-5 ℃ and reacting for 48 hours. Cooling to 20 deg.C, carefully discharging the gas in the kettle, transferring the reaction solution to a flask, evaporating the solvent under reduced pressure, adding methyl tert-butyl ether into the residue, heating to 40 deg.C, stirring for 2 hr, cooling, filtering, and washing the filter cake with methyl tert-ether to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid as white solid with optical purity of 92%.
Example 5.9: using the method of example 5.8, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a pressure cooker.
Example 5.10: to a 3L three-necked flask, 1L of 0.1mol/L Tris/HCl buffer solution and 1L isooctane were added, followed by 282.3g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 242.4g of (S) - α -phenylethylamine, 24.7g of pyridoxal phosphate and 0.5g of transaminase I (derived from Polaromonas sp.). Stirring at 35-38 deg.C for 48hrs, filtering, washing the filter cake with small amount of isooctane, recrystallizing the filter cake with methanol to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid with yield of 85% and e.e% > 99%.
Example 5.11: using the method of example 5.10, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a beaker.
Example 5.12: to a 3L three-necked flask, 1L of 0.1mol/L Tris/HCl buffer and 1L isooctane were added, followed by 282.3g of the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenylyl) pentanoic acid obtained in example 4, 242.4g of (S) - α -phenylethylamine, 24.7g of pyridoxal phosphate and 1.5g of transaminase II (derived from Burkholderia graminis). Stirring at 35-38 deg.C for reaction for 96hrs, filtering, washing the filter cake with small amount of isooctane, recrystallizing the filter cake with methanol to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid with yield of 40% and e.e% > 99%.
Example 5.13: using the method of example 5.12, (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) valerate having an optical purity of greater than 98% was obtained by adding the compound (2R) -2-methyl-4-carbonyl-5- (4' -biphenyl) valerate obtained in example 4 to a beaker.
Example 6: synthesis of Sacubitril
Example 6.1: 11g (0.04mol) of the compound (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid obtained in example 5 and 200mL of ethanol were put in a three-necked flask, cooled to 5 ℃ C. + -. 5, and 9.5g (0.08mol) of thionyl chloride was added dropwise thereto, and after completion of the addition, the temperature was raised to 60 ℃ C. + -. 5 to react for 24 hours. Cooling the reaction liquid to 20 ℃, and adding a saturated sodium carbonate solution to neutralize the reaction liquid; and then 4.4g (0.044mol) of succinic anhydride is added in batches, the temperature is kept at 25 ℃ for 8h of reaction, after the reaction is finished, the reduced pressure distillation is carried out, the solvent is removed by concentration, 2M HCl is added into the residue until the pH is =3-4, ethyl acetate is used for extraction, an organic phase is dried by anhydrous magnesium sulfate and filtered, and the filtrate is concentrated to obtain 12.1g of Sacubitril with the yield of 73%.
Example 6.2: 0.04mol of (2R,4S) -2-methyl-4-amino-5- (4 '-biphenyl) pentanoate, the compound obtained in example 5, was hydrolyzed in 10ml of aqueous hydrochloric acid to obtain (2R,4S) -2-methyl-4-amino-5- (4' -biphenyl) pentanoic acid, and Sacubitril 11.5g was prepared in 69% yield using the method of example 6.1.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (4)
1. A synthesis method of an enkephalinase inhibitor intermediate shown as a formula I is characterized in that a compound shown as a formula II is subjected to asymmetric reduction ammoniation reaction to obtain a compound shown as a formula I,
wherein R is H, methyl and ethyl, the compound of formula II is reacted under the action of chiral ruthenium catalyst to obtain the compound of formula I, and the chiral ruthenium catalyst is Ru [ (S) -BINAP (OAc)2]Or Ru (OAc)2[(S)-MeO-BIPHEP]。
2. The process as claimed in claim 1, wherein the compound of the formula II is subjected to an asymmetric reductive amination reaction with ammonium acetate and hydrogen to give the compound of the formula I.
3. The method of claim 2, wherein the compound of formula II is prepared from a compound of formula III:
wherein R is H, methyl or ethyl; r1 is H, methyl or ethyl.
4. A process according to claim 3, characterized in that the compound of formula III is prepared from a compound of formula IV:
wherein R is H, methyl or ethyl; r1 is H, methyl or ethyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610540043.8A CN107602399B (en) | 2016-07-11 | 2016-07-11 | Preparation method of enkephalinase inhibitor intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610540043.8A CN107602399B (en) | 2016-07-11 | 2016-07-11 | Preparation method of enkephalinase inhibitor intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107602399A CN107602399A (en) | 2018-01-19 |
| CN107602399B true CN107602399B (en) | 2020-09-25 |
Family
ID=61055256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610540043.8A Active CN107602399B (en) | 2016-07-11 | 2016-07-11 | Preparation method of enkephalinase inhibitor intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107602399B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3386955B1 (en) * | 2015-12-10 | 2020-08-05 | Novartis AG | Intermediates for the preparation of sacubitril and their preparation |
| CN109071407A (en) | 2016-02-29 | 2018-12-21 | 广东东阳光药业有限公司 | One seed sand library must be bent intermediate and preparation method thereof |
| CN112174798B (en) * | 2019-07-03 | 2023-08-08 | 山东科巢生物制药有限公司 | Synthesis method of Sakuba/valsartan sodium LCZ696 |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0555175A1 (en) * | 1992-01-22 | 1993-08-11 | Ciba-Geigy Ag | Biaryl substituted 4-amino-butyric acid amides |
| CN101631765A (en) * | 2007-01-12 | 2010-01-20 | 诺瓦提斯公司 | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| CN102448928A (en) * | 2009-05-28 | 2012-05-09 | 诺瓦提斯公司 | Substituted Aminobutyric Derivatives as Neprilysin Inhibitors |
| CN103313708A (en) * | 2010-11-16 | 2013-09-18 | 诺瓦提斯公司 | Method of treating contrast-induced nephropathy |
| EP2148886B1 (en) * | 2007-05-10 | 2014-02-19 | R & D Biopharmaceuticals Gmbh | Tubulysine derivatives |
| CN104230865A (en) * | 2013-06-13 | 2014-12-24 | 上海翰森生物医药科技有限公司 | Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof |
| CN104557600A (en) * | 2015-01-26 | 2015-04-29 | 苏州明锐医药科技有限公司 | Preparation method of sacubitril |
| CN105601524A (en) * | 2016-03-17 | 2016-05-25 | 海门慧聚药业有限公司 | Preparation method of LCZ696 key intermediate |
| CN105924355A (en) * | 2016-05-11 | 2016-09-07 | 浙江宏元药业有限公司 | Sacubitril intermediate and preparation method of sacubitril intermediate and sacubitril |
| CN106977415A (en) * | 2016-01-15 | 2017-07-25 | 广东东阳光药业有限公司 | One planting sand storehouse must be bent intermediate and preparation method thereof |
| CN108602785A (en) * | 2015-12-10 | 2018-09-28 | 诺华股份有限公司 | New technique and intermediate |
| CN109071407A (en) * | 2016-02-29 | 2018-12-21 | 广东东阳光药业有限公司 | One seed sand library must be bent intermediate and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106795537A (en) * | 2014-06-16 | 2017-05-31 | 英威达技术有限责任公司 | Method, reagent and cell for biosynthesis compound |
-
2016
- 2016-07-11 CN CN201610540043.8A patent/CN107602399B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0555175A1 (en) * | 1992-01-22 | 1993-08-11 | Ciba-Geigy Ag | Biaryl substituted 4-amino-butyric acid amides |
| CN101631765A (en) * | 2007-01-12 | 2010-01-20 | 诺瓦提斯公司 | Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid |
| EP2148886B1 (en) * | 2007-05-10 | 2014-02-19 | R & D Biopharmaceuticals Gmbh | Tubulysine derivatives |
| CN102448928A (en) * | 2009-05-28 | 2012-05-09 | 诺瓦提斯公司 | Substituted Aminobutyric Derivatives as Neprilysin Inhibitors |
| CN103313708A (en) * | 2010-11-16 | 2013-09-18 | 诺瓦提斯公司 | Method of treating contrast-induced nephropathy |
| CN104230865A (en) * | 2013-06-13 | 2014-12-24 | 上海翰森生物医药科技有限公司 | Biaryl-substituted 4-aminobutyric acid derivatives, and preparation method and application thereof |
| CN104557600A (en) * | 2015-01-26 | 2015-04-29 | 苏州明锐医药科技有限公司 | Preparation method of sacubitril |
| CN108602785A (en) * | 2015-12-10 | 2018-09-28 | 诺华股份有限公司 | New technique and intermediate |
| CN106977415A (en) * | 2016-01-15 | 2017-07-25 | 广东东阳光药业有限公司 | One planting sand storehouse must be bent intermediate and preparation method thereof |
| CN109071407A (en) * | 2016-02-29 | 2018-12-21 | 广东东阳光药业有限公司 | One seed sand library must be bent intermediate and preparation method thereof |
| CN105601524A (en) * | 2016-03-17 | 2016-05-25 | 海门慧聚药业有限公司 | Preparation method of LCZ696 key intermediate |
| CN105924355A (en) * | 2016-05-11 | 2016-09-07 | 浙江宏元药业有限公司 | Sacubitril intermediate and preparation method of sacubitril intermediate and sacubitril |
Non-Patent Citations (2)
| Title |
|---|
| Kinetic resolution of aromatic b-amino acids by x-transaminase;Han-Seop Bea etal;《Chem. Commun.》;20111231;第1-8页 * |
| Sam Mathew etal.Production of chiral amino acids using ω-transaminase fromBurkholderia graminis from Burkholderia graminis.《Journal of Biotechnology》.2015,第1-8页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107602399A (en) | 2018-01-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107805205B (en) | Preparation method of (R) -3-aminobutanol | |
| CN107602399B (en) | Preparation method of enkephalinase inhibitor intermediate | |
| CN113004142B (en) | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid | |
| CN106432030A (en) | Preparation method of brivaracetam | |
| CN108675943A (en) | The preparation method of one planting sand library Ba Qu key intermediates | |
| CN103183673B (en) | The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane | |
| CN111574380B (en) | Method for preparing 5,5 '-disubstituted-2, 2' -diaminobiphenyl and hydrochloride thereof by reduction coupling method | |
| CN110878099B (en) | Preparation method of pyrrole [1,2, alpha ] indole alkaloid derivative | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN106187787B (en) | A kind of preparation method of 2- amino -4- chlorodiphenyl ether | |
| CN103896826B (en) | The method of asymmetric synthesis of (3R, 4R)-3-methylamino-4-methyl piperidine of nitrogen protection, relevant intermediate and method for preparing raw material | |
| JPH11508271A (en) | Preparation of 5-formylvaleric acid | |
| CN102516233B (en) | Method for producing voriconazole | |
| CN113527081B (en) | Preparation method of 3-oxocyclobutanecarboxylic acid | |
| CN106117204B (en) | The preparation method of the carboxylic acid of Lei Dipawei intermediates (1R, 3S, 4S) 2 Boc 2 azabicyclo [2.2.1] pentane 3 | |
| CN114805167A (en) | Preparation method of brivaracetam | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN110668958B (en) | Method for preparing (R) -3-aminobutanol | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN102363598B (en) | Method for preparing high-purity gabapentin | |
| CN112812033A (en) | Novel synthesis method of oseltamivir | |
| CN105294479A (en) | Preparation method of 3R-amino substituted butyrylamide derivative | |
| CN104230880A (en) | Simple preparation method of 2-((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxyhexacyclo-4-yl)acetate | |
| CN100509838C (en) | Method for producing 5 alpha-pregnane derivative | |
| CN115286504B (en) | Method for synthesizing (R) -2- (2- (tert-butoxy) -2-oxyethyl) pentanoic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 330700 Fengxin Industrial Park Fengxin County Yichun city Jiangxi Province Patentee after: Jiangxi Boteng Pharmaceutical Co.,Ltd. Address before: 330700 Fengxin Industrial Park Fengxin County Yichun city Jiangxi Province Patentee before: JIANGXI DONGBANG PHARMACEUTICAL Co.,Ltd. |